Cardiovascular Agents

1. Cardiovascular Agents Michael Perez

2. Cardiovascular Disease • These are various and have innumerable amounts of treatments and drugs used in treatment • Focus on hypertension and angina (chest pain.)

3. Hypertension and angina • Both of these can be caused by constriction of the blood vessels in the body, or simply by an increase in blood flow in a vessel that isn’t dilated completely. This of course causes hypertension directly (high blood pressure) and leads to chest pains if these vessels deliver blood to the heart.

4. Nitric Oxide • Discovered in the early 1980’s. • A molecule that acts as a hormone by being formed in response to a signal, causing the smooth muscles surrounding blood vessels to relax. • Causes blood pressure to go down • Mechanism of action not completely understood

5. NO Synthesis in Body • Nitric oxide is formed by the oxidation of l-arginine via an enzyme called nitric oxide synthase. • The NOS enzyme uses NADPH and oxygen as cosubstrates • The NOS enzyme catalyzes a five-electron oxidation of Argenine to NO and L-citrullline using NADH as the source of electrons. • NOS produces NO in response to increased calcium ion concentrations.

6. NOS • The enzyme is divided into reductase and oxygenase domains with the central part of the protein containing a consensus sequence for calcium/calmodulin binding.

7. Mechanism of Synthesis

8. Simpler Reaction

9. Possible NO Mechanism • This is not definitive, but is considered the most likely way NO works: • target protein for nitric oxide is guanylyl cyclase, enzyme that generates cyclic GMP from GTP by causing a conformational change in guanylyl cyclase by binding to the allosteric site on the enzyme. • Cyclic GMP causes cylic GMP dependent kinase to become activated, which phosphorylates myosin light-chain kinase, making it inactive. This renders it unable to interact with calcium ions that bind to calmodulin and prevents phosphorylation of myosin that interacts with actin to cause the contraction of smooth muscle.

10. Nitro-vasodilator Drugs • These are metabolized into NO in the body by an unknown reactions. • Ascanio Sobrero in Turin, Italy, first discovered nitroglycerine in 1847. Sobrero noticed that strong headaches were a direct result of small quantites of agent placed on the tongue. • Constantin Hering in 1849 tested nitroglycerine on volunteers. Hering believed that nitroglycerine might be used to relieve headaches through the notion that “like cures like.”

11. Nitroglycerine • In 1867 William Murrell first used nitroglycerine to treat angina. • In 1977, Ferid Murad discovered the release of nitric oxide from nitroglycerine, causing vascular smooth muscle to dilate.

12. Sodium Nitroprusside • Nitroprusside consists of iron and cyanide groups. • When liberation of cyanide takes place, the drug is metabolized in the mitochondria. Cyanide doesn’t cause toxic effects because it is converted to thiocyanate. The kidney later excretes thiocyanate. • Sodium nitroprusside is used for the treatment of hypertensive emergencies, and is given intravenously. Most frequently given early in the treatment of acute heart failure.

13. Side Effects and Downfalls • Patients have shown resistance to nitroglycerine and other vasodilators, like amyl nitrate, after long periods of use. • Thiocyanate accumulation occurs, more often in patients with kidney problems after prolonged nitroprusside infusion causing nausea, disorientation, psychosis and muscle spasms.

14. Calcium Channel Antagonists • These drugs have become the alternative as of late to nitro-vasodilators in treating hypertension and angina. • These act in much the same way, only they directly block calcium from being released by cells that later binds to calmodulin, preventing phosphorylation of myosin that interacts with actin to cause smooth muscle contraction.

15. Drugs and their receptor target • Antagonists target the voltage-dependent L-type calcium channels that release the calcium ions responsible for cardiac and smooth muscle contraction. • Bind the calcium channel and prevent it from releasing calcium ions.

16. Dihydropyrdines • Nifedipine • Selective for smooth vascular muscle over cardiac muscle and quick results • Short acting • Some instances of heart attacks and mortality • Different group of dihydropyridines have longer effects

17. DHP Structure • Chemical structure requirement for these 1, 4-DHP agents to be active as antagonists: • First, an aromatic ring is placed at the top of the general nifedipine structure, which is attached to the C-4 position. • Optimal to have the phenyl ring substituted at the ortho-postion by an electron withdrawing substituent. Studies have shown that a bulky substituent at this position is favorable.

18. Modifications for Antagonsim • X-ray diffraction revealed that the DHP has boat type conformation with a distortion at the c-4 postion and affects the antagonistic nature greatly • Ester groups in the C-3 and C-5 positions also increase antagonist activity

19. Conformational Representation of DHP

20. L-Type Calcium Channel • Here is the transmembrane receptor and the binding sites of different antagonists are shown.

21. Diphenylalkylamines • Verapamil is most common • Acts at different site of L-type channel • Equally selective for cardiac and vascular smooth muscle • Risk of undesirable myocardial depression

22. Potential Drug Improvements • Mibefradil • A tetralol derivative has been developed from rougly 500 derivatives of verapamil. This drug showed selectivity between vascular and cardiac tissues during assay screening and some clinical studies using a guinea pig heart. Still in trials.